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Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P< 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P< 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P= 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P= 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P= 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients.

Introduction: During the last decades, improvements in the treatment of transfusion-dependent thalassemia (TDT) with safer transfusion schemas, improved management of iron overload and of comorbidities, have resulted in significantly increased life expectancy. With increased survival, the pattern of characteristics of death is changing.

No relevant conflicts of interest to declare.

The diagnosis of beta thalassemia intermedia (BTI) is mainly based on the severity of clinical phenotype. It is associated with a wide range of specific complications including extramedullary hematopoiesis, leg ulcers, gallstones, hypercoagulable state, pulmonary hypertension (PHT), endocrine disorders and osteoporosis. The commonest endocrine complication in beta thalassemia major (TM) patients is hypogonadism followed by hypothyroidism and diabetesbut the data on endocrine disorders in BTI patients are scarce. The aim of this study is to determine the prevalence of endocrine complications in a large series of BTI patients.

Despite the recent availability of multiple therapeutic options for chelation therapy, severe iron overload remains a significant cause of morbidity and mortality in a small group of patients with thalassemia major (TM). Every effort to induce negative iron balance for these patients is warranted. In this context, combination of deferasirox (DFX) and deferoxamine (DFO) may be of significant value. In this report, we present the paregoric use of DFX and DFO in severely iron overloaded thalassemic patients.Five patients (3 Males, 2 females) have been treated with DFX and DFO as a last rescue measure. In these patients previous combined treatment with DFO and DFP had failed. Informed consent and approval for the use of this schema as paregoric therapy was obtained by patients and hospital. The main inclusion criteria for this treatment were: LIC>30 mg/gr d. w. and T2* cardiac <10 msec. Treatment consisted of daily DFX at 30–40 mg/kg/day and DFO at 40–50 mg/kg/day for 3–6 days/week.Patients' characteristics, results and toxicity are shown in table 1 and 2. Improvement in iron load status ranged widely during a follow-up from 1 to 3 yrs. LIC reduced in 4/5 patients, cardiac T2* increased in 3/5 patients, while LVEF showed no significant changes. Ferritin levels improved in 2/5 patients. Deterioration of safety parameters necessitated not to discontinue treatment.These data in the use of combination therapy of DFX and DFO suggest a potential modality of chelation therapy in severely iron overloaded patients. Response was variable and seemed not to be always related to compliance or the duration of treatment. Increase of serum creatinin and AST in all patients is a considerable problem in patients with persistent significant iron overload and already impaired hepatic and renal function, despite having been treated with different schema of iron chelation. Longer and cautious follow-up is needed to come to reliable conclusions.Ladis: Novartis: Consultancy, Honoraria, Research Funding; Apopharma: Consultancy, Honoraria, Research Funding. Kattamis:Apopharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Abstract 5181

The introduction of iron chelation treatment has led to a significant improvement in morbidity and overall survival in patients with transfusion-dependent anemias. Deferasirox is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in both adult and pediatric patients. The efficacy and safety of deferasirox in a variety of transfusion-dependent anemias has been established in numerous Phase II/III clinical trials. Since most patients with transfusion-dependent anemias require lifelong iron chelation therapy, there is a need to assess the long-term safety of deferasirox in both adult and pediatric patients.To assess the safety profile of deferasirox in patients with transfusional iron overload in a real-world clinical setting. To further investigate the safety profile of deferasirox in patients with congenital erythrocyte disorders and transfusional iron overload, with ferritin levels <4000 ng/ml and without severe cardiac siderosis.Between July 2009 and September 2010, 85 patients with transfusion-induced iron overload treated with deferasirox as per the approved product labeling were enrolled in the study. These data represent the 24-week planned interim analysis of a 12-month observational study on deferasirox safety profile in the treatment of pediatric and adult patients with transfusion-dependent anemias who were newly-treated with deferasirox. Safety was evaluated through the monitoring and recording of all adverse events and serious adverse events, as well as routine laboratory testing, including hematology, blood chemistry and hepatic function assessments.The population had a median age of 37.6 years (range: 5.3–61.4) and a female to male ratio of 1.3. Beta-thalassemia (67.1%) was the most common transfusion-dependent anemia, followed by thalassemia intermedia requiring periodic transfusions (20.0%) and sickle cell anemia (12.9%). Mean baseline ferritin levels were 1502.1±870.5 (pediatric group: 1480.2±522.8 and adult group: 1503.6±891.4), while 53 out of the 85 patients (62.4%) had serum ferritin level above 1000 ng/ml. Mean baseline liver T2* value was 10.4±9.7 ms; 44.4% of patients demonstrated minimal liver iron deposition (MRI T2* > 6.3 ms), 51.4% had mild to moderate liver iron overload (T2* ≤ 6.3 ms), and 4.2% had severe liver iron overload (T2*<1.4 ms).54 (63.5%) of patients analysed had been pre-treated with iron chelators and 31 (36.5%) were chelation-naïve. The initial average daily dose of deferasirox was 25.9±4.8 mg/kg, and 70.6% of patients had no dose modification during the 24-week follow-up period. A statistical significant decrease in median serum ferritin levels was observed by Week 24 (mean absolute change from baseline:-214.5 ng/mL; p=0.009) [Figure 1]. No statistically significant changes were observed in creatitine levels, creatinine clearance and transaminases by Week 24 [Figure 1].37 ADRs were reported by 17 patients (20%) over the 24-week period. Among the most frequently observed ADRs (>5%) were epigastralgia reported by 7.1% of patients (6/85) and loose stools/diarrhoea by 5.9% of patients (5/85). The majority of ADRs reported (nevents=25; 67.6%) were graded as mild in severity, while 21.6% (nevents=8) were graded as moderate and 10.8% (nevents=4) as severe. Most ADRs (nevents=31; 83.8%) resulted in full recovery by Week 24. The overall incidence of SADRs was as low as 1.2% (in particular one patient experienced severe epigastralgia and upper extremity pain which resulted in her withdrawal from the study after four months of treatment). The all-cause discontinuation rate was 9.4% (8/85), while only two patients (2.4%) discontinued the study therapy due to ADR; 1 patient due to increased transaminase levels and 1 patient due to the aforementioned SADR.These data highlight the safety profile of deferasirox in both adult and pediatric patients; the regular monitoring of serum ferritin levels as well as other iron-overload parameters and transfusion requirements play a major role in determining and optimizing the outcome of iron chelation therapy.Ladis: Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Drossou:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Vini:Novartis Pharmaceuticals: Investigator participating in a trial sponsored by Novartis. Athanasiou-Metaxa:Novartis Hellas S.A.C.I.: Research Funding. Oikonomou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Vlachaki:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Tigka:Novartis Hellas S.A.C.I.: Employment. Tzavelas:Novartis Hellas S.A.C.I.: Employment. Liakopoulou:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Adamopoulos:Novartis Hellas S.A.C.I.: Investigator participating in a trial sponsored by Novartis. Kattamis:Novartis Hellas S.A.C.I.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

New modalities for the assessment of iron overload and the availability of new oral chelators have led to important changes in the iron load status and its treatment for patients with thalassemia major (TM). The goals of this retrospective analysis were to evaluate the changes that occurred in regards to the degree of iron overload, as well as to the therapeutic regimen of iron chelation over the last decade in young patients with TM.All patients with TM followed in our unit, who were <18 years at certain time points, were included in this study. Group A included all patients who were younger than 18 years old on 1/1/2001, while group B, C, D, E and F on 1/1/2003, 1/1/2005, 1/1/2007, 1/1/2009, and 1/1/2011, respectively. Liver iron concentration (LIC) and cardiac siderosis (T2*) were evaluated by MRI. Cardiac iron concentration (CIC) was calculated based on the recently prescribed formula CIC= 45 × (T2*Heart)−1.22.The closest MRI, which was <12 months from the time point, was recorded for each patient at each group. The therapeutic regimen for iron chelation, being deferoxamine (DFO), deferiprone (DFP), combination therapy of DFO and DFP (DFO+DFP) and deferasirox (DFX), used at the different time points were also recorded.The results of the analysis are shown in the following table:Ferritin levels did not change significantly over the last decade (p>0.05). There was a trend for decreasing values of LIC (Independent Samples Kruskal-Wallis test, p=0.075) with the mean LIC of group E and F being significantly lower than group C (Mann-Whitney test, p<0.05). Similarly, there was a trend for improvement in the indexes of cardiac iron load. Of note is, that cardiac overload was not documented in this group of patients. None of the patients has significant (T2*<10 msec), and only 3 patients had moderate cardiac siderosis (T2*>10 <20 msec).A steady decrease in the number of young patient with thalassemia has been observed, reflecting the efficacy of the thalassemia prevention program. As expected, the utilization of MRI to evaluate iron overload has increased significantly especially in the second part of the last decade, but it remains limited mainly to older children and teenagers. Oral chelation has become the preferable mode of treatment of hemosiderosis in young patients with TM. While DFX is, currently, the most used iron chelator, the use of DFO is becoming limited as an additive therapy to DFP. Despite presumed better compliance with oral chelation therapy, the iron overload indexes have not improved dramatically. This may reflect the short period of using the oral chelators or/and the need for further treatment intensification.Kattamis: Novartis Oncology: Honoraria, Research Funding, Speakers Bureau; Apopharma: Honoraria.

Abstract 3183

Abstract 3202

Recent advances in the treatment of iron overload in patients with transfusion- dependent thalassemia have dramatically changed iron related morbidity and mortality. Intensive chelation therapy by using combination therapy or monotherapy at high doses had led to total clearing of the iron in many patients. The best approach for chelation treatment in patients with low levels of iron overload is debatable.This study included all the patients with thalassemia major with minimal liver iron overload, followed in our unit. More precisely, to be eligible for this observational study, the patients needed to have liver iron concentration (LIC) <1.5 mg Fe/gram dry weight tissue, defined by MRI, and to have at least a subsequent MRI evaluation after this time. The mean observation time, which was the time between the two MRIs, was 16.9±5.2 months.Fourty five patients (22 females, 30 non-splemectomized, 21 HCV seropositive, mean age: 31±5.6 years) have reached minimal levels of iron overload in any time point after 2004. Thirty one of them have been treated with combined therapy of desferrioxamine (DFO) and deferiprone (DFP) and 5, 6 and 3 with monotherapy of deferasirox (DFX), DFP and DFO, respectively. After reaching these levels, 42% of the patients changed therapy, with the most frequent change being from combined therapy to monotherapy (15 patients).Baseline ferritin levels at the time of the first MRI range from 43 to 4336 ng/ml (median 230 ng/ml) and they were not affected by spleen, gender or HCV status. Baseline LIC (mean 1.2 ± 1.7 mgFe/g.d.w.) correlated well with ferritin levels (Spearman's rho = 0.47, p<0.005), as did ferritin changes to LIC changes (Spearman's rho = 0.67, p<0.005).The results on the follow up evaluation, stratified according to the actual treatment, are shown in the tableDeferiprone was less efficacious in controlling both LIC and ferritin levels compared to combination therapy (p=0.016 and 0.031, respectively). Fifteen out of 17 patients treated with DFP showed an increase in LIC, despite using the recommended dose. Six out of 9 patients treated with DFX, most at a low dose, showed an increase in LIC. There were no differences in changes in the cardiac parameters (LVEF, cardiac T2*) in between treatment groups. The efficiency of DFP and DFX, which represents the ratio of iron excreted to the theoretical maximum of iron that could be bound by the chelators, was calculated at 1.8±0.9 % and 15.2 ± 3.6 %, respectively.Current iron chelation therapy regimens are able to render iron load-free many patients with thalassemia major. As iron accumulation from transfusions continues, a fine balance needs to be found in which neither worsening of iron overload nor toxicity from excessive dose of iron chelators will occur. This study showed that at low levels of iron overload both combination therapy and DFX can control iron accumulation, whether monotherapy with DFP may be insufficient to achieve iron balance in many patients. The dose of the chelators needs to be adjusted according to the needs and the clinical course of the patients, which can be predicted by the trend of the ferritin levels. Furthermore, it should be kept in mind that at low levels of iron overload, the iron chelators' efficiency may be lower than previously described.Kattamis: NOVARTIS ONCOLOGY: Honoraria, Research Funding, Speakers Bureau; APOPHARMA: Honoraria. Ladis:NOVARTIS ONCOLOGY: Honoraria, Research Funding; APOPHARMA: Honoraria, Research Funding.

Abstract 4270

241 thalassemia major patients have had repeated evaluation of cardiac iron assessed by Magnetic Resonance Imaging (MRI) over a median interval of 15 months (range 2.6–72.6). We compared changes in T2* between MRI studies with desferrioxamine (DFO) – (number of patients (n)=31, total MRIs (nMRI)=116), deferiprone (DFP) − (n=41 nMRI=94) and combination of DFO and DFP (Comb) − (n=143 nMRI=347) using repeated measurement analysis with correlated error terms and time varying covariates. Patients were divided into four groups according to their baseline cardiac T2* (Heavy load £ 8 ms, moderate load 8–14, mild 314–20 and normal 320). Table 1 shows the overall assessment excluding patients on DFX. These were not included in that assessment as the total period of exposure was statistically significantly less than that of the other regimes. Analysis was therefore performed using student T test to assess the rate of change between the first and second MRI in the T2* values in patients with comparable cardiac siderosis according to each chelation regime adjusted for overall time of exposure (Table 2). With linear regression analysis (Table3) we compared the effect of DFO to the other three regimes in the annual rate of increasing cardiac T2*. The results have been adjusted for baseline T2* and time of exposure to therapy. Both DFP and Comb regimes are superior to DFO in reducing cardiac siderosis. This indicates that over one year DFP and Comb regimes will have a greater increase in T2* than that achieved by DFO. In addition, Comb seems to be superior to DFX as it would increase the T2* by 2ms/year above that which can be achieved by DFX (p=0.007). DFP achieves 1.7ms/year above the annual improvement with DFX but the difference is not statistically significant. The estimated difference in annual improvement of T2* between Comb and DFP is 0.33ms/year (p=0.07) These data confirm that which is seen in clinical practice according to the chelation regimes used. It is clear that the combination of DFO and DFP is the most rapid regime for reducing cardiac iron and seems to be effective at all levels of cardiac siderosis. The ability to assess tissue iron in the heart is extremely clinically valuable and allows preemptive intervention in order to reduce cardiac morbidity and mortality by the selection of the most appropriate chelation therapy according to the MRI findings. Table1 Annual estimated mean change in T2* according to severity of cardiac siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2* p ΔT2* p DFO 0.61 n.s 1.06 n.s. −1.5 n.s. DFP 0.55 <0.001 2.8 <0.001 3.4 <0.001 Comb 1.4 <0.001 3.5 <0.001 2.6 <0.001 Table 2 Annual estimated mean change in T2* according to severity of cardiac siderosis Regime Heavy Moderate Mild ΔT2* P ΔT2* p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 73 tm*= 23 0.73 0.05 1.07 0.09 0.9 0.4 DFP n= 53 tm=18.5 1.95 0.14 3.2 0.0045 3.9 0.06 Comb n= 152 tm=21.2 1.98 <0.001 4.4 <0.001 5.7 0.0025 DFX n=96 tm=14.9 −0.51 0.41 −0.67 0.4 4.2 0.23 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO 2.1 0.99 0.033 Comb v DFO 2.4 0.69 <0.001 DFX v DFO 0.44 0.82 0.6

241 thalassemia major patients have had repeated evaluation of cardiac iron assessed by Magnetic Resonance Imaging (MRI) over a median interval of 15 months (range 2.6–72.6). We compared changes in T2* between MRI studies with desferrioxamine (DFO) – (number of patients (n)=31, total MRIs (nMRI)=116), deferiprone (DFP) − (n=41 nMRI=94) and combination of DFO and DFP (Comb) − (n=143 nMRI=347) using repeated measurement analysis with correlated error terms and time varying covariates. Patients were divided into four groups according to their baseline cardiac T2* (Heavy load £ 8 ms, moderate load 8–14, mild 314–20 and normal 320). Table 1 shows the overall assessment excluding patients on DFX. These were not included in that assessment as the total period of exposure was statistically significantly less than that of the other regimes. Analysis was therefore performed using student T test to assess the rate of change between the first and second MRI in the T2* values in patients with comparable cardiac siderosis according to each chelation regime adjusted for overall time of exposure (Table 2). With linear regression analysis (Table3) we compared the effect of DFO to the other three regimes in the annual rate of increasing cardiac T2*. The results have been adjusted for baseline T2* and time of exposure to therapy. Both DFP and Comb regimes are superior to DFO in reducing cardiac siderosis. This indicates that over one year DFP and Comb regimes will have a greater increase in T2* than that achieved by DFO. In addition, Comb seems to be superior to DFX as it would increase the T2* by 2ms/year above that which can be achieved by DFX (p=0.007). DFP achieves 1.7ms/year above the annual improvement with DFX but the difference is not statistically significant. The estimated difference in annual improvement of T2* between Comb and DFP is 0.33ms/year (p=0.07) These data confirm that which is seen in clinical practice according to the chelation regimes used. It is clear that the combination of DFO and DFP is the most rapid regime for reducing cardiac iron and seems to be effective at all levels of cardiac siderosis. The ability to assess tissue iron in the heart is extremely clinically valuable and allows preemptive intervention in order to reduce cardiac morbidity and mortality by the selection of the most appropriate chelation therapy according to the MRI findings.

There is strong evidence that reactive oxygen species (ROS) are involved in the pathogenesis of thalassaemias. It has been shown that ROS are generated in increased amounts in thalassemic erythrocytes following the precipitation of excess unmatched globin chains and the deposition of non-heme iron and hemichromes. Continuous ROS production in thalassemic individuals may alter their overall redox status and cause tissue damage. Reduction in the levels of vitamin C, vitamin E, and carotenoids has been reported in beta-thalassemic patients receiving transfusion therapy. In this study we investigated the oxidative stress in relation to the degree of erythropoiesis in patients with beta-thalassemia Intermedia (TI). Forty patients with TI were included in the study. Sixteen patients had mild anemia and mild clinical phenotype. The remaining 24 patients had more severe phenotype, but rare transfusions had been used in only 8 of them. Non-transferrin-bound iron (NTBI) levels were determined using graphite furnace atomic absorption spectrometry. Lipid peroxidation expressed as malonyldialdehyde (MDA) concentration was measured by reverse-phase HPLC with fluorimetric detection. The erythroid marrow activity was estimated by measuring soluble transferrin receptors (sTfR) levels with a turbidimetric technique. The main results of the study showed thatNTBI and MDA levels were increased (normal controls <0.05micromol/L and <0.65 micromol/L respectively) in 32/40 patients, while sTfR was found 4- to 20-fold higher than normal in all patients,NTBI, MDA and sTFR levels were significantly higher in patients with the more severe phenotype compared with patients with the milder phenotype (p<0.01),NTBI correlated positively: with MDA (rho=0.502, p<0.003), with sTfR (rho=0.371, p<0.02) and Hb F (rho=0.464, p<0.005), while no correlation was found between NTBI and Hb levels (p>0.278) andMDA was correlated significantly with Hb F (rho=0.464, p<0.005), while the correlation with sTfR levels was poor (rho=0.313, p<0.05). Patients with thalassemia intermedia have increased MDA levels, suggestive of imbalanced oxidant/antioxidant equilibrium. This phenomenon seems to be related to altered iron homoestasis, especially with the increased levels of NTBI. NTBI induces ROS production mainly through the Fenton reaction. NTBI levels are affected by the severity of tissue hypoxia, as these were expressed by their positive correlations with levels of sTfR, MDA and Hb F. The following hypothesis may be explain our findings; increased Hb F leads to tissue hypoxia, which induces further erythropoetic activity, as this is expressed by increased sTfR levels. Increased erythropoetic activity, possibly through a negative effect on hepcidin production (Kattamis et al, Haematologica91: 809–12, 2006) results in increased NTBI levels, which lead to increased ROS production and MDA levels. Further studies are required to validate this hypothesis that altered iron cycle contributes to the oxidant/antioxidant imbalance observed in thalassemia intermedia.

There is strong evidence that reactive oxygen species (ROS) are involved in the pathogenesis of thalassaemias. It has been shown that ROS are generated in increased amounts in thalassemic erythrocytes following the precipitation of excess unmatched globin chains and the deposition of non-heme iron and hemichromes. Continuous ROS production in thalassemic individuals may alter their overall redox status and cause tissue damage. Reduction in the levels of vitamin C, vitamin E, and carotenoids has been reported in beta-thalassemic patients receiving transfusion therapy. In this study we investigated the oxidative stress in relation to the degree of erythropoiesis in patients with beta-thalassemia Intermedia (TI). Forty patients with TI were included in the study. Sixteen patients had mild anemia and mild clinical phenotype. The remaining 24 patients had more severe phenotype, but rare transfusions had been used in only 8 of them. Non-transferrin-bound iron (NTBI) levels were determined using graphite furnace atomic absorption spectrometry. Lipid peroxidation expressed as malonyldialdehyde (MDA) concentration was measured by reverse-phase HPLC with fluorimetric detection. The erythroid marrow activity was estimated by measuring soluble transferrin receptors (sTfR) levels with a turbidimetric technique. The main results of the study showed thatNTBI and MDA levels were increased (normal controls <0.05micromol/L and <0.65 micromol/L respectively) in 32/40 patients, while sTfR was found 4- to 20-fold higher than normal in all patients,NTBI, MDA and sTFR levels were significantly higher in patients with the more severe phenotype compared with patients with the milder phenotype (p<0.01),NTBI correlated positively: with MDA (rho=0.502, p<0.003), with sTfR (rho=0.371, p<0.02) and Hb F (rho=0.464, p<0.005), while no correlation was found between NTBI and Hb levels (p>0.278) andMDA was correlated significantly with Hb F (rho=0.464, p<0.005), while the correlation with sTfR levels was poor (rho=0.313, p<0.05).